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Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid Malignancies

From the Institute for Drug Development, Cancer Therapy and Research Center, and University of Texas Health Science Center at San Antonio, San Antonio, TX; Dana-Farber Partners in Cancer Care, Boston, MA; Cancer Institute of New Jersey, New Brunswick; Knoll Pharmaceutical Company, Mount Olive, NJ.

Address reprint requests to Miguel A. Villalona-Calero, MD, Arthur G. James Cancer Hospital, Ohio State University, B406 Starling-Loving Hall, 320 West 10^th Ave, Columbus, OH 43210-1240; email: villalona-1{at}medctr.osu.edu

PURPOSE: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks.

PATIENTS AND METHODS: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course.

RESULTS: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m²/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m²/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m²/d dose level. At the 18-mg/m²/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment.

CONCLUSION: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m²/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.

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